Interplay of G-proteins and Serotonin in the Neuroimmunoinflammatory Model of Chronic Stress and Depression: A Narrative Review

Abstract

Introduction: This narrative review addresses the clinical challenges in stress-related disorders such as depression, focusing on the interplay between neuron-specific and pro-inflammatory mechanisms at the cellular, cerebral, and systemic levels. Objective: We aim to elucidate the molecular mechanisms linking chronic psychological stress with low-grade neuroinflammation in key brain regions, particularly focusing on the roles of G proteins and serotonin (5-HT) receptors. Methods: This comprehensive review of the literature employs systematic, narrative, and scoping review methodologies, combined with systemic approaches to general pathology. It synthesizes current research on shared signaling pathways involved in stress responses and neuroinflammation, including calcium-dependent mechanisms, mitogen-activated protein kinases, and key transcription factors like NF-κB and p53. The review also focuses on the role of G protein-coupled neurotransmitter receptors (GPCRs) in immune and pro-inflammatory responses, with a detailed analysis of how 13 of 14 types of human 5-HT receptors contribute to depression and neuroinflammation. Results: The review reveals a complex interaction between neurotransmitter signals and immunoinflammatory responses in stress-related pathologies. It highlights the role of GPCRs and canonical inflammatory mediators in influencing both pathological and physiological processes in nervous tissue. Conclusion: The proposed Neuroimmunoinflammatory Stress Model (NIIS Model) suggests that proinflammatory signaling pathways, mediated by metabotropic and ionotropic neurotransmitter receptors, are crucial for maintaining neuronal homeostasis. Chronic mental stress can disrupt this balance, leading to increased pro-inflammatory states in the brain and contributing to neuropsychiatric and psychosomatic disorders, including depression. This model integrates traditional theories on depression pathogenesis, offering a comprehensive understanding of the multifaceted nature of the condition.

Exploring the Pathophysiology of Long COVID: The Central Role of Low-Grade Inflammation and Multisystem Involvement

“…This form of inflammation is not characterized by the inflammatory focus’s barrier function and can generalize within tissues and the body during chronic progression, leading to stable allostasis [ 88 ]. Low-grade inflammation arises in response to moderately damaging factors such as metabolites (meta-inflammation) [ 89 , 90 ], aging (inflamm-aging) [ 91 , 92 ], endotoxin generalization with intestinal barrier and microbiome disruption [ 93 ], and excitotoxicity [ 94 , 95 ]. It may underlie many somatic and neuropsychiatric disorders, including chronic stress, depression, neurodegeneration, and schizophrenia [ 94 , 95 , 96 , 97 ].…”

“…Increased levels of IL-6 and CRP during simultaneous reactivation of CMV and EBV are noted, particularly in the context of neuropsychiatric stress and, occasionally, depression [ 184 ]. It is important to recognize that psychoemotional stress and depression can lead to immune dysfunction and further exacerbate low-grade inflammation [ 95 ]. Additionally, patients with the highest CMV antibody titers exhibit an increased mortality risk from cardiovascular diseases and all-cause mortality, a relationship partly explained by moderately elevated levels of IL-6 and TNF-α [ 185 ].…”

“…Despite the CNS’s inherent protections—such as barriers, immune privilege, non-reliance on potentially lipotoxic fatty acids for bioenergetics, and limited microglial activity akin to stromal macrophages—these defenses do not completely prevent damage [ 95 ]. Moreover, the CNS’s high metabolic rate and intensive transmembrane cation transport necessitate robust protective mechanisms to maintain physiological pro-inflammatory tone under both normal and extreme physiological conditions.…”

“…Moreover, the CNS’s high metabolic rate and intensive transmembrane cation transport necessitate robust protective mechanisms to maintain physiological pro-inflammatory tone under both normal and extreme physiological conditions. Notably, almost all types of neurotransmitters acting through metabotropic G-protein-coupled receptors (GPCRs) can stimulate cellular stress signaling pathways in neurons ( Figure 2 ) [ 95 ].…”

“…Such parallels enhance our understanding of potential common mechanisms underlying these conditions and could guide targeted interventions and support for affected groups. Importantly, PTSD is one of the complications of chronic mental stress, which in turn is linked to low-grade inflammation [ 95 , 201 ], potentially explaining the overlap of many neurogenic symptoms between LC and PTSD.…”